This invention relates to processes for the regioselective preparation of heterocyclo-alkylsulfonyl pyrazole derivatives and their synthetic intermediates. The pyrazole compounds prepared by the processes of this invention are useful in the treatment or alleviation of inflammation and other inflammation associated disorders, such as arthritis, neurodegeneration and colon cancer, in mammals, preferably humans, dogs, cats or livestock. It is believed that the pyrazole compounds prepared by the processes of this invention inhibit the biosynthesis of prostaglandins by intervention of the action of the enzyme cyclooxygenase on arachidonic acid.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in treating pain and the signs and symptoms of arthritis because of their analgesic and anti-inflammatory activity. It is accepted that common NSAIDs work by blocking the activity of cyclooxygenase (hereinafter referred to as “COX”), also known as prostaglandin G/H synthase (PGHS), the enzyme that converts arachidonic acid into prostanoids. Prostaglandins, especially prostaglandin E2 (PGE2), which is the predominant eicosanoid detected in inflammation conditions, are mediators of pain, fever and other symptoms associated with inflammation. Inhibition of the biosynthesis of prostaglandins has been a therapeutic target of anti-inflammatory drug discovery.
A variety of sulfonylbenzene compounds which inhibit COX have been disclosed in patent publications (WO 97/16435, WO 97/14691, WO 96/19469, WO 96/36623, WO 96/03392, WO 96/03387, WO 97/727181, WO 96/936617, WO 96/19469, WO 96/08482, WO 95/00501, WO 95/15315, WO 95/15316, WO 95/15317, WO 95/15318, WO 97/13755, EP 0799523, EP 418845, and EP 554829). International Publication Number WO 97/11704 discloses pyrazole compounds substituted by optionally substituted aryl.
The production of the compounds of formula 1 with a yield and purity suitable for commercial use has presented several difficulties. As described in detail below, the use of previously disclosed methods results in the production of significant amounts of the regioisomer of the compound of formula 1, which is difficult to separate from the compound of formula 1 without significant loss of yield. Applicants' investigations have revealed that preparing the compound of formula 1 at low temperatures favors the regioselective production of the compound of formula 1 but provides poor yields and the presence of an intermediate as a major impurity. On the other hand, maintaining the reaction temperature high enough to allow the consumption of the intermediates causes another problem, namely, the production of the regioisomer of the compound of formula 1.
Applicants solved these problems by discovering unexpectedly that the use of water as a co-solvent in the reaction provided the following benefits: (1) the production of the regioisomer of the compound of formula 1 is minimized, thereby resulting in the formation of the compound of formula 1 with high regioselectivity; and (2) the compound of formula 1 is formed with high yield. In addition, the use of water allows the regioselective production of the compound of formula 1 over a broad range of temperatures.